1. Field of the Invention
The invention relates to a novel process for hydroxymethylating noncyclic α,α-dialkylcarboxylic acid derivatives with formaldehyde using amide bases at temperatures of from −40° C. up to the boiling point of the solvent or solvent mixture used.
The target compounds are suitable as intermediates for preparing polymers and active pharmaceutical ingredients and thus of great industrial and economic interest.
2. Background Art
The prior art discloses a series of processes for hydroxymethylating α,α-dialkylcarboxylic acid derivatives. The general principle of the reactions known from the prior art is the use of formaldehyde as the hydroxymethylating reagent in the presence of a base, predominantly those from the class of the amide bases, at low temperatures. It is known in particular that α,α-dialkylcarboxylic esters, after deprotonation with lithium diisopropylamide (LDA), can be reacted with formaldehyde, to give the corresponding α,α-dialkyl-α-hydroxymethylcarboxylic esters at low temperatures.
Derrick L . J . Clive et al. (Tetrahedron Letters 43 (2002), p. 4559-4563) and Gerard N. LeFevre et al. (Journal of the American Chemical Society 108 (1986), p. 1019-1027) each describe a process for hydroxymethylating a norbornene derivative with paraformaldehyde. Both for the generation of the enolate of the ester used as the starting compound (ester enolate) with LDA and in the further reaction of the thus generated enolate with paraformaldehyde, it is necessary to employ very low temperatures of −78° C. in order to achieve a significant conversion. The product yields are nevertheless only 43% and 61% respectively.
The reaction of structurally closely related cyclohexanoic esters and cyclopentanoic esters with lithium diisopropylamide and gaseous formaldehyde has been described by Michiharu Kato et al. (Chemistry Letters (1985), p. 1785-1788), S. Richard Baker et al. (Tetrahedron Letters 40 (1999), p. 781-784) and B. R. Neustadt et al. (J. Med. Chem. 37 (1994), p. 2461-2467). Both for the generation of the ester enolate with LDA and for the further reaction with formaldehyde, very low temperatures of −78° C. are again also employed in this process.
The conversion of an α,α-dialkylcarboxylic ester at higher temperatures has been achieved only by the use of a very specific and expensive base, since no reaction whatsoever is otherwise observed under non-low-temperature conditions. George R. Pettit et al. (Synthetic Communications 11(3), 1981, p. 167-177) describe the deprotonation of a cyclohexane carboxylic ester with trityllithium and subsequent hydroxymethylation of the enolate formed with paraformaldehyde at ice-bath temperatures. The authors suspected that the formation of the carbanion in this case is particularly difficult and therefore a specific base for deprotonation, such as trityllithium, has to be used.
The hydroxymethylation of a free α,α-dialkylcarboxylic acid by generation of the enolate with an excess of LDA and reaction with gaseous formaldehyde has been described using the example of a cyclohexane carboxylic acid derivative by F. E. Ziegler et al. (Organic Letters 2 (2000), p. 3619-3622). However, in this process too, very low temperatures of −78° C. again have to be employed.
With knowledge of the prior art, the skilled person can thus draw the inference that, for the successful hydroxymethylation of the α,α-dialkylcarboxylic acid derivatives described therein with formaldehyde using amide bases, temperatures of −78° C. are obligatory. When higher reaction temperatures are desired, a reaction can be achieved only when specific and expensive bases are used, for example trityllithium.
For a large-scale or industrial hydroxymethylation reaction of α,α-dialkylcarboxylic acid derivatives, however, both the need to employ low-temperature conditions and/or the use of specific and costly reagents are afflicted with great technical and economic disadvantages.
Moreover, the prior art does not disclose any analogous hydroxymethylation reactions of α,α-dialkylcarboxylic acid derivatives, in which the carbon atom in the α-position to the carboxyl group is not part of a cyclic hydrocarbon system, since the substrates described in the prior art derive exclusively from cyclopentane, cyclohexane or norbornene carboxylic acid derivatives. The hydroxymethylation of α,α-dialkylcarboxylic acid derivatives which do not have this structural feature has not been described to date in the prior art. In particular, the hydroxymethylation of open-chain substrates, for example 2-ethylhexanoic acid and its derivatives, with formaldehyde has not yet been described.
Thus, whether the hydroxymethylation of α,α-dialkylcarboxylic acid derivatives in which the carbon atom α to the carboxyl group is not part of a cyclic hydrocarbon system is possible at all, or whether specific procedures would be required with such substrates, were unknown. Indeed, the prior art suggests that hydroxymethylations are possible exclusively with carboxylic acid derivatives in which the carbon atom α to the carboxyl group is part of a cyclic hydrocarbon system, and even then, the process must take place under low-temperature conditions or with the use of specific reagents.